Genetic variation of the IL-28B promoter affecting gene expression.
Genetic variation of the IL-28B promoter affecting gene expression.
复制标题
DOI：
10.1371/journal.pone.0026620
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Mizokami M
中科院分区：
文献类型：
--
作者：
Sugiyama M;Tanaka Y;Wakita T;Nakanishi M;Mizokami M
目前治疗慢性丙型肝炎的标准治疗是聚乙二醇干扰素-α（PEG-IFNα）和利巴韦林（RBV）。该治疗仅在约50%的患者中实现了持续的病毒清除。最近的全基因组关联研究显示，IL-28 B周围的单核苷酸多态性（SNP）与标准治疗的反应相关，并可预测约80%的治疗反应。然而，目前还不清楚哪一个SNP是最具信息性的，因为含有显著SNP的基因组区域显示出强烈的连锁不平衡。我们专注于与IL-28 B基因紧密接近的SNP，以评估每个SNP的功能，并鉴定对IL-28 B表达水平影响最大的SNP。通过cDNA全序列克隆，确定IL-28 A/B 5 ′-UTR的结构。IL-28 A和28 B基因均由6个外显子组成，与NCBI的CCDS数据不同。两个内含子SNP和一个非同义SNP不影响IL-28 B基因的功能和表达水平，但位于近端启动子区的SNP影响基因表达。通过对IL-28 B上游近端SNPs的功能研究发现，启动子区存在一个（TA）二核苷酸重复序列rs72258881，该序列在IFN-α和脂多糖刺激后转录活性呈（TA）n长度依赖性增加。健康的日本供体表现出广泛的（TA）二核苷酸重复数从10到18，最普遍的基因型是12/12（75%），不同于数据库（13/13）。然而，在这些日本供体中未检测到与IL-28 B对应的IL-28 A遗传变异。这些发现表明，二核苷酸重复序列可能与IL-28 B的转录活性相关，也可能是改善对基于干扰素的丙型肝炎病毒治疗反应的预测的标志物。
The current standard of care for the treatment of chronic hepatitis C is pegylated interferon-α (PEG-IFNα) and ribavirin (RBV). The treatment achieves a sustained viral clearance in only approximately 50% of patients. Recent whole genome association studies revealed that single nucleotide polymorphisms (SNPs) around IL-28B have been associated with response to the standard therapy and could predict treatment responses at approximately 80%. However, it is not clear which SNP is most informative because the genomic region containing significant SNPs shows strong linkage disequilibrium. We focused on SNPs in close proximity to the IL-28B gene to evaluate the function of each and identify the SNP affecting the IL-28B expression level most. The structures of IL-28A/B from 5′ to 3′-UTR were determined by complete cDNA cloning. Both IL-28A and 28B genes consisted of 6 exons, differing from the CCDS data of NCBI. Two intron SNPs and a nonsynonymous SNP did not affect IL-28B gene function and expression levels but a SNP located in the proximal promoter region influenced gene expression. A (TA) dinucleotide repeat, rs72258881, located in the promoter region was discovered by our functional studies of the proximal SNPs upstream of IL-28B; the transcriptional activity of the promoter increased gradually in a (TA)n length-dependent manner following IFN-α and lipopolysaccharide stimulation. Healthy Japanese donors exhibited a broad range of (TA) dinucleotide repeat numbers from 10 to 18 and the most prevalent genotype was 12/12 (75%), differing from the database (13/13). However, genetic variation of IL-28A corresponding to that of IL-28B was not detected in these Japanese donors. These findings suggest that the dinucleotide repeat could be associated with the transcriptional activity of IL-28B as well as being a marker to improve the prediction of the response to interferon-based hepatitis C virus treatment.
登录
查看更多内容
影响因子：
3.8
作者：
Bartlett, NW;Buttigieg, K;Smith, GL
通讯作者：
Smith, GL
影响因子：
4.4
作者：
Ank, Nina;Iversen, Marie B.;Paludan, Soren R.
通讯作者：
Paludan, Soren R.
影响因子：
158.5
作者：
Ribic, CM;Sargent, DJ;Gallinger, S
通讯作者：
Gallinger, S
影响因子：
29.4
作者：
Rauch, Andri;Kutalik, Zoltan;Bochud, Pierre-Yves
通讯作者：
Bochud, Pierre-Yves
DOI：
10.1073/pnas.95.14.8170
发表时间：
1998-07-07
影响因子：
11.1
作者：
Beutler, E;Gelbart, T;Demina, A
通讯作者：
Demina, A